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Bioorganic Chemistry 105 (2020) 104352
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Abstract: |
PDE5 targeting represents a new and promising strategy for apoptosis induction and inhibition of tumor cell
growth due to its over-expression in diverse types of human carcinomas. Accordingly, we report the synthesis of
series of pyrazolo[3,4-d]pyrimidin-4-one carrying quinoline moiety (11a-r) with potential dual PDE5 inhibition
and apoptotic induction for cancer treatment. These hybrids were structurally elucidated and characterized with
variant spectroscopic techniques as 1H NMR, 13C NMR and elemental analysis. The assessment of their anticancer
activities has been declared. All the rationalized compounds 11a-r have been selected for their cytotoxic activity
screening by NCI against 60 cell lines. Compounds 11a, 11b, 11j and 11k were the most active hybrids. Among
all, compound 11j was further selected for five dose tesing and it displayed outstanding activity with strong
antitumor activity against the nine tumor subpanels tested with selectivity ratios ranging from 0.019 to 8.3 at the
GI50 level. Further, the most active targets 11a, b, j and k were screened for their PDE5 inhibitory activity,
compound 11j (with IC50 1.57 nM) exhibited the most potent PDE5 inhibitory activity. Moreover, compound 11j
is also showed moderate EGFR inhibition with IC50 of 5.827 ± 0.46 μM, but significantly inhibited the Wnt/
β-catenin pathway with IC501286.96 ± 12.37 ng/mL. In addition, compound 11j induced the intrinsic apoptotic
mitochondrial pathway in HepG2 cells as evidenced by the lower expression levels of the anti-apoptotic Bcl-2
protein, and the higher expression of the pro-apoptotic protein Bax, p53, cytochrome c and the up-regulated
active caspase-9 and caspase-3 levels. All results confirmed by western blotting assay. Compound 11j exhibit
pre G1 apoptosis and cell cycle arrest at G2/M phase. In conclusion, hybridization of quinoline moiety with the
privileged pyrazolo[3,4-d]pyrimidinon-4-one structure resulted in highly potent anticancer agent, 11j, which
deserves more study, in particular, in vivo and clinical investiagtions, and it is expected that these results would
be applied for more drug discovery process.
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